SPECIFIC AIMS I) Using a MTHFR-deficient mouse model, to determine whether the gender difference in the risk of colorectal cancer is related to differences in the status of one-carbon and/or folate metabolism. II) If I) is true, to determine whether the effect of female gender on the one-carbon metabolism is conveyed through the female hormone, estrogen. III) If I) and II) are true, to determine whether alterations in one-carbon metabolism affect the DNA methylation status of estrogen receptor genes as well as expression of these genes. IV) If I), II) and III) are true, to determine whether these molecular and biochemical changes by estrogen affect the development of colorectal cancer in the apc1638N mouse model.